P868: MEZIGDOMIDE (MEZI) PLUS DEXAMETHASONE (DEX) IN PATIENTS (PTS) WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): RESULTS FROM THE DOSE-EXPANSION PHASE OF THE CC-92480-MM-001 TRIAL
Authors: Nizar J Bahlis, Suzanne Trudel, Hang Quach, Rakesh Popat, Sagar Lonial, Robert Z Orlowski, Kihyun Kim, Maria-Victoria Mateos, Charlotte Pawlyn, Karthik Ramasamy, Joaquín Martinez-Lopez, Ignacio Casas-Avilés, Alessia Spirli, Jing Gong, Michael Amatangelo, Jessica Katz, Paulo Maciag, Teresa Peluso, Paul Richardson
Journal: HemaSphere (2023)

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: MEZI, a novel oral cereblon E3 ligase modulator (CELMoD™) with enhanced tumoricidal and immune-stimulatory effects compared with IMiD® agents, induces maximal Ikaros/Aiolos degradation, leading to increased apoptosis in MM cells. Preclinically, MEZI demonstrated potent synergy with DEX, proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs). In phase 1 of CC-92480-MM-001 (NCT03374085), the recommended phase 2 dose (RP2D) of MEZI + DEX (Mezi-d) was selected at 1 mg once daily for 21/28 days. Aims: To report results from the Mezi-d dose-expansion cohort in pts with heavily pretreated RRMM. Methods: Eligible pts had: RRMM; ≥3 prior lines of therapy; refractoriness to lenalidomide (LEN)/pomalidomide (POM), a PI, a glucocorticoid, and an anti-CD38 mAb; disease progression in ≤60 days of last myeloma therapy. MEZI 1 mg was given on days 1–21 of each 28-day cycle, with weekly DEX (40 mg; 20 mg if >75 years of age). Primary objective was to evaluate efficacy by overall response rate (ORR); secondary objectives included safety/tolerability and additional efficacy assessments. Pharmacodynamics was an exploratory objective. Results: As of September 16, 2022, 101 pts had received MEZI-d at the RP2D. Median age was 67 (range 42–85) years, median time since initial diagnosis was 7.4 (1.1–37.0) years, and 20.8% of pts had ISS stage III at study entry. Plasmacytomas were present in 39.6% of pts and 37/101 pts had high-risk cytogenetics (56/101 pts not evaluable). Median number of prior regimens was 6 (range 3–15). Prior therapies included stem cell transplantation (77.2%) and anti-B-cell maturation antigen (BCMA) therapy (29.7%). All pts were refractory to last myeloma regimen and triple-class refractory, and 39.6% of pts were refractory to LEN, POM, ≥ 2 PIs, and an anti-CD38 mAb. Median follow-up was 7.46 (range 0.5–21.9) months, with a median number of 4 (1–20) cycles received; 10 (9.9%) pts continued treatment, with the main reason for discontinuation being progressive disease (60.4%). ORR was 40.6% in all pts (Table). While data are not yet mature, median progression-free survival (PFS) was 4.4 (95% confidence interval [CI] 3.0–5.5) months and median duration of response was 7.6 (95% CI 5.4–9.5) months. In pts with plasmacytomas, ORR was 30.0% (n=40) and median PFS was 3.0 (95% CI 2.1–4.9) months. In pts with prior anti-BCMA therapy, ORR was 50.0% (n=30) and median PFS was 5.4 (95% CI 2.1–9.4) months. Grade (Gr) 3/4 treatment-emergent adverse events (TEAEs) were reported in 92 (91.1%) pts. Most frequent (≥20% pts) hematologic Gr 3/4 TEAEs were neutropenia (75.2%, with 14.9% febrile neutropenia), anemia (35.6%), and thrombocytopenia (27.7%). Gr 3/4 infections were seen in 34.7% of pts, including Gr 3/4 pneumonia (15.9%) and COVID-19 (7.0%). Other Gr 3/4 non-hematologic TEAEs were generally low, including gastrointestinal disorders (5.9%), fatigue (5.0%), and rash (1.0%). Due to TEAEs, 76 (75.2%) pts and 29 (28.7%) pts had MEZI dose interruptions and reductions, respectively. MEZI induced substrate degradation and increases in activated and proliferating T cells in all pts, including in pts refractory to POM-containing therapies, demonstrating the efficacy of MEZI in this heavily pretreated population. Summary/Conclusion: MEZI-d had a manageable safety profile with encouraging efficacy in pts with triple-class refractory RRMM, including pts with prior BCMA-targeted therapies. These results support the development of MEZI in MM. MEZI is being evaluated in combination with standard therapies in MM in an ongoing phase 1/2 trial (NCT03989414); phase 3 trials in combination with PIs are planned.Keywords: Clinical data, Multiple myeloma, Immunomodulation